As noted above, in response to the concern about the appropriate diagnosis for children with chronic, severe irritability, we defined a group of children whom we described as having severe mood dysregulation (SMD). These children have extremely severe irritability and symptoms of hyperarousal (the latter being similar to those seen in attention deficit hyperactivity disorder (ADHD)) and, although they frequently receive the diagnosis of bipolar disorder (BD), they do not indeed meet diagnostic criteria for BD. Since the inception of this project, approximately 200 youth with SMD have been recruited into the project. Approximately 20 new patients were recruited this year. It is very important to note that these youth with SMD suffer very severe psychiatric impairment, and indeed are as ill as are youth with BD in terms of number of medications prescribed, number of psychiatric hospitalizations, and standardized measures of function. Also as noted above, in previous years we demonstrated differences between youth with SMD and those with BD in terms of clinical course, family history, and the brain mechanisms associated with behavioral problems. This year we gathered more data to support the conclusion that, while youth with SMD and those with BD both have severe mood disorders, the two groups differ in the nature of their brain dysfunction. In prior work, we demonstrated that youth with BD or SMD, but not those with other psychiatric illnesses, have deficits in face emotion labeling. This year we published data supporting previous findings indicating that, while BD and SMD have similar deficits in face labeling, the neural mechanisms mediating face emotion processing differ between groups. Specifically, when viewing angry faces, youth with BD showed decreased amygdala activation relative to youth with SMD or healthy subjects. This publication is in press. Consistent with this, in another study being prepared for publication, we found that, in healthy subjects, amygdala activity varied in response to increasing degrees of anger on a face, but that youth with BD and those with SMD both fail to show such brain modulation by the emotional content of the face. This failure to modulate brain activity in response to the level of emotion in a stimulus is consistent with the clinical presentation of these patient populations, which is characterized by an inability to modulate emotional responses. In addition to this work on face processing, this year we also compared the groups on brain activity during a task that requires subjects to respond flexibly to changes in which of their behaviors are rewarded. Both of our patient populations show deficits on such response flexibility tasks, and it is possible that these deficits contribute to the frustration experienced by youth with SMD. That is, youth with SMD may become frustrated and irritable because they are unable to respond appropriately to ever-changing environmental demands. Using fMRI in conjunction with a response reversal paradigm, we found that youth with SMD differed from healthy subjects and those with BD on activation in the inferior frontal gyrus, a brain region that is centrally involved in response flexibility. Given the central role that excessive responses to frustration play in the symptomatology of SMD, additional neuroimaging studies focus very directly on the brain dysfunction associated with frustration in SMD. Specifically, this year we published data comparing youth with SMD, those with BD, and healthy subjects on magnetoencephalography (MEG) measures obtained while the children played a frustrating game. Like fMRI, MEG is a noninvasive neuroimaging technique;the advantage of MEG is that it has exquisite temporal resolution. The results of this MEG study indicated that, during the game, youth with SMD reported more frustration than did BD or healthy subjects. In addition, in response to negative feedback, SMD experienced greater activation in the medial frontal gyrus and anterior cingulate cortex than did the other two groups. This indicates that negative feedback may be particularly salient to youths with SMD. Consistent with this, preliminary data from an fMRI study using the same task indicates that, when frustrated, youth with SMD experience considerable dysfunction in brain regions mediating attention (these data are currently being prepared for publication). This raises the possibility that a treatment aimed at training irritable youth to control their attention more effectively when frustrated might have therapeutic effects, although considerably more research needs to be conducted to confirm the feasibility and appropriateness of this approach. The fact that youth with SMD share many symptoms with youth with attention deficit hyperactivity disorder (ADHD), as well as an increasing emphasis on dimensional, rather than categorical, classification in psychiatry, is an important impetus for a new research approach that we began to adopt this year and will continue in the coming year. Consistent with the Research Domain Criteria initiative of the NIMH, this year we laid groundwork so that our research in the next year will adopt a dimensional approach to irritability, studying not just youth with SMD and healthy youth, but also youth with different levels of irritability. And, in doing so, we will control for the fact that SMD youth have ADHD symptoms. That is, we will recruit youth with ADHD and varying levels of irritability, as well as those with SMD, to participate in studies designed to further elucidate the brain mechanisms mediating frustration. Finally, from a public health perspective, it is essential to determine whether the distinction between SMD and BD, which is evident in terms of clinical course, family history, and neural circuitry, is also associated with between-group differences in treatment response. In previous work, we found that lithium was not effective in the treatment of SMD. Last year, we began a double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor antidepressant) plus stimulant is more effective than placebo plus stimulant in the treatment of SMD. Thus far, we have randomized approximately 20 children into the trial, and youth are tolerating the experimental treatment well.